Novel form of Alzheimer's protein found in spinal fluid indicates stage
of the disease
Discovery could lead to better diagnostics, speed efforts to find
treatment

Date:
December 7, 2020
Source:
Washington University School of Medicine
Summary:
Researchers have found a novel form of the Alzheimer's protein tau
in the fluid surrounding the brain and spinal cord. This form of
tau -- known as MTBR tau -- indicates what stage of Alzheimer's
a person is in and tracks with tangles of tau protein in the brain.



FULL STORY ==========================================================================
A novel form of an Alzheimer's protein found in the fluid that surrounds
the brain and spinal cord indicates what stage of the disease a person
is in, and tracks with tangles of tau protein in the brain, according
to a study from researchers at Washington University School of Medicine
in St. Louis. Tau tangles are thought to be toxic to neurons, and their
spread through the brain foretells the death of brain tissue and cognitive decline. Tangles appear as the early, asymptomatic stage of Alzheimer's develops into the symptomatic stage.


==========================================================================
The discovery of so-called microtubule binding region tau (MTBR tau)
in the cerebrospinal fluid could lead to a way to diagnose people in
the earliest stages of Alzheimer's disease, before they have symptoms
or when their symptoms are still mild and easily misdiagnosed. It also
could accelerate efforts to find treatments for the devastating disease,
by providing a relatively simple way to gauge whether an experimental
treatment slows or stops the spread of toxic tangles.

The study is published Dec. 7 in the journal Brain.

"This MTBR tau fluid biomarker measures tau that makes up tangles and
can confirm the stage of Alzheimer's disease by indicating how much
tau pathology is in the brains of Alzheimer's disease patients," said
senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. Bateman treats patients with
Alzheimer's disease on the Washington University Medical Campus. "If we
can translate this into the clinic, we'd have a way of knowing whether
a person's symptoms are due to tau pathology in Alzheimer's disease
and where they are in the disease course, without needing to do a brain
scan. As a physician, this information is invaluable in informing patient
care, and in the future, to guide treatment decisions." Alzheimer's
begins when a brain protein called amyloid starts forming plaques in the
brain. During this amyloid stage, which can last two decades or more,
people show no signs of cognitive decline. However, soon after tangles
of tau begin to spread in the neurons, people start exhibiting confusion
and memory loss, and brain scans show increasing atrophy of brain tissue.

Tau tangles can be detected by positron emission tomography (PET) brain
scans, but brain scans are time-consuming, expensive and not available everywhere.

Bateman and colleagues are developing diagnostic blood tests for
Alzheimer's disease based on amyloid or a different form of tau, but
neither test can pin down the amount of tau tangles across the stages
of disease.

MTBR tau is an insoluble piece of the tau protein, and the primary
component of tau tangles. Bateman and first author Kanta Horie, PhD,
a visiting scientist in Bateman's lab, realized that specific MTBR tau
species were enriched in the brains of people with Alzheimer's disease,
and that measuring levels of the species in the cerebrospinal fluid that
bathes the brain might be a way to gauge how broadly the toxic tangles
have spread through the brain. Previous researchers using antibodies
against tau had failed to detect MTBR tau in the cerebrospinal fluid. But
Horie and colleagues developed a new method based on using chemicals to
purify tau out of a solution, followed by mass spectrometry.

Using this technique, Horie, Bateman and colleagues analyzed cerebrospinal fluid from 100 people in their 70s. Thirty had no cognitive impairment
and no signs of Alzheimer's; 58 had amyloid plaques with no cognitive
symptoms, or with mild or moderate Alzheimer's dementia; and 12 had
cognitive impairment caused by other conditions. The researchers found
that levels of a specific form -- MTBR tau 243 -- in the cerebrospinal
fluid were elevated in the people with Alzheimer's and that it increased
the more advanced a person's cognitive impairment and dementia were.

The researchers verified their results by following 28 members of the
original group over two to nine years. Half of the participants had some
degree of Alzheimer's at the start of the study. Over time, levels of
MTBR tau 243 significantly increased in the Alzheimer's disease group,
in step with a worsening of scores on tests of cognitive function.

The gold standard for measuring tau in the living brain is a tau-PET
brain scan. The amount of tau visible in a brain scan correlates with
cognitive impairment. To see how their technique matched up to the gold standard, the researchers compared the amount of tau visible in brain
scans of 35 people - - 20 with Alzheimer's and 15 without -- with levels
of MTBR tau 243 in the cerebrospinal fluid. MTBR tau 243 levels were
highly correlated with the amount of tau identified in the brain scan, suggesting that their technique accurately measured how much tau --
and therefore damage -- had accumulated in the brain.

"Right now there is no biomarker that directly reflects brain tau
pathology in cerebrospinal fluid or the blood," Horie said. "What
we've found here is that a novel form of tau, MTBR tau 243, increases continuously as tau pathology progresses. This could be a way for us
to not only diagnose Alzheimer's disease but tell where people are in
the disease. We also found some specific MTBR tau species in the space
between neurons in the brain, which suggests that they may be involved
in spreading tau tangles from one neuron to another. That finding opens
up new windows for novel therapeutics for Alzheimer's disease based on targeting MTBR tau to stop the spread of tangles."

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kanta Horie, Nicolas R Barthe'lemy, Chihiro Sato, Randall J
Bateman. CSF
tau microtubule binding region identifies tau tangle and
clinical stages of Alzheimer's disease. Brain, 2020 DOI:
10.1093/brain/awaa373 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/12/201207091304.htm

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